We develop and apply novel technologies for label-free, microscopic, three-dimensional imaging of various vascular and cellular dynamics, including blood flow, cellular viability, and neuronal activity. Our approaches are mainly based on, but not limited to, optical coherence tomography (OCT), the latest innovation milestone in the history of biomedical engineering as recognized by American Institute for Medical and Biological Engineering.

Photonic Neural Interface

Neural interfaces refer to the application of targeted electrical, chemical, and biological technologies to the nervous system in order to improve function and quality of life. Depending on the applied technology, neural interfaces can either read information from or write signals into the nervous system. Examples include neuroprosthetics for quadriplegia patients (reading), retinal prostheses (writing), and closed-loop deep brain stimulation (both). The most advanced neural interfaces approved to date by the Food and Drug Administration (FDA) for use in human clinical studies are based on electrical recording and stimulation through implants, which consist hundreds of passive wire electrodes, substantially larger in size and pitch than the underlying neurons, drastically limiting the amount and quality of information that can be read from the human brain. These electrode-based technologies are also limited in terms of safety, due to invasiveness that potentially leads to tissue damage, and in terms of long-term usability due to cellular encapsulation that causes degradation in the recording sensitivity. Non-invasive neuroimaging technologies, such as functional magnetic resonance imaging, have spatial and temporal resolution insufficient for identifying individual neurons and spikes. Here, we investigate novel ideas for label-free, cellular-resolution imaging and/or stimulation of neuronal activity in vivo.

Neurovascular Coupling

Brain consumes energy. The oxygen and glucose supplied by cerebral blood flow (CBF) must be regulated to meet metabolic needs of neurons that vary location by location and moment to moment. This energy supply regulation is critical for normal brain functioning and fundamental for interpreting human neuroimaging data. Inadequate blood flow supply occurs in various disorders such as ischemic stroke, hypertension, and Alzheimer’s disease. The current paradigm for understanding this energy supply regulation focuses on how local neural activity leads to arteriolar dilation through smooth muscle cells, and thus, increased blood flow to activated neural tissue. This paradigm is recently being challenged by two unanswered questions: (1) the precise spatial scale over which neural and vascular signals are correlated is unknown; and (2) whether capillaries, which lack smooth muscle cells, actively participate in CBF regulation. We study these questions using our latest techniques for microscopic in vivo imaging of CBF in both arteries and capillaries with unprecedented resolution and scale.

Ischemic Stroke

Ischemic stroke is a major healthcare problem and one of the leading causes of mortality and morbidity around the world. Although it is one of the most frequent causes of emergency admissions, there is only one FDA-approved treatment option for acute stroke treatment: recombinant tissue plasminogen activator (rt-PA). Unfortunately, the time window for rt-PA application is very short (up to 3-4.5 h) and the success rate is low. Furthermore, only a small percentage of rt-PA administered patients shows both recanalization and reperfusion; reperfusion cannot be attained in about a quarter of the recanalized patients. Therefore, there is a critical need to determine the underlying mechanisms responsible for unsuccessful reperfusion. We investigate the mechanisms in the stroke animal model using our microscopic in vivo imaging techniques. 

Cellular Viability Imaging

Normal functioning of cells critically depends on intracellular energy synthesis, and thus the energy metabolism-related cellular viability can be an important measurand. Label-free imaging of the cellular viability with single-cell resolution, however, is technically challenging despite its potential for wide applications. Here, we test if our recently developed technology can provide a means to image the cellular viability. The technology has been developed by integrating dynamic light scattering (DLS) with optical coherence tomography (OCT). DLS analyzes fluctuations in light scattered by particles to measure diffusion or flow of the particles, and OCT uses coherence gating to collect light only scattered from a small volume for high-resolution structural imaging. Thus, our integration of DLS and OCT enabled high-resolution 3D mapping of the diffusion coefficient and flow velocity. The diffusion map may quantify the movement of intracellular organelles, the degree of which depends on the cellular viability.